Project Summary Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent disease of the nails, skin, and oral and genital mucosae, caused by the fungus Candida albicans. The pathogenesis of CMC disease (CMCD), a genetic form of CMC, has long remained elusive. Our identification of autosomal recessive (AR) IL-17RA and autosomal dominant (AD) IL-17F deficiencies paved the way for that of AR IL-17RC and ACT1 deficiencies in other patients with isolated CMCD, and of AR ROR-? deficiency and AD STAT1 gain-of-function (GOF) in patients with a broader phenotype of syndromic CMCD. We showed that cells from patients with IL-17RA, IL- 17RC, and ACT1 deficiencies did not respond to IL-17A/F. In addition, IL-17RA- and ACT1-, unlike IL-17RC- deficient cells, did not respond to IL-17E. Moreover, patients with ROR-? deficiency and STAT1 GOF displayed low proportions of IL-17A/F-producing T cells, both ex vivo and after in vitro differentiation. We have reported 85 patients with a genetic etiology of CMCD, out of a total of 188 published cases. We have also enrolled 317 other patients with isolated or syndromic CMCD, from 245 kindreds, originating from 30 countries, whom we hypothesize carry CMCD-causing mutations. We intend to search for mutations in the six known CMCD-causing genes (IL17F, IL17RA, IL17RC, ACT1, RORC, and STAT1), in order to delineate the associated molecular, cellular, immunological, and clinical phenotypes. We also intend to pursue our search for novel CMCD-causing genes using genome-wide (GW) approaches, based on GW linkage (GWL), and whole-exome or whole- genome sequencing (WES/WGS); we will prioritize mutations in genes that control the response to, or the production of, IL-17A/F. This program is built on our pioneering effort in the human genetic dissection of CMCD by cutting-edge genomic and immunological methods, some of which have been developed in the laboratory. We have recently obtained surprising and exciting preliminary results. We found 12, 3, and 121 new patients with IL-17RA, ACT1, and STAT1 mutations, respectively. We also identified three novel genetic etiologies. We discovered AD JNK1 deficiency in three patients from a kindred with syndromic CMCD, whose cells do not respond to IL-17A/F; this is the first inborn error of MAPK-dependent immunity. We also discovered AR c-REL and ZNF341 deficiencies in syndromic CMCD patients from one and two kindreds, respectively, whose cells do not produce IL-17A/F; c-REL is a member of the NF-?B family and ZNF341 is a completely novel protein. These preliminary data neatly illustrate the validity of our approaches, and the potential of our integrated research. Our project is highly innovative, yet supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable and novel insights into the mechanisms of mucocutaneous immunity to fungi, including the role of IL-17 cytokines. This work will also shed light on the pathogenesis of CMCD, making it possible to provide molecular diagnoses for patients and genetic counseling for families. This new information will facilitate the use of IL-17 or other cytokines for the treatment of CMC, in addition to antifungal agents.